Mangold J B, Rodriguez L C, Wang Y K
Drug Metabolism and Pharmacokinetics Department, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Drug Metab Dispos. 1995 Jun;23(6):615-21.
Cyclosporin G (CsG; Sandoz compound OG 37-325) is a cyclic undecapeptide with potent, immunosuppressive activity and is currently in clinical testing for prevention of transplanted solid organ rejection. Although structurally similar to cyclosporin A (CsA), results in animals suggest that CsG has a reduced potential for nephrotoxicity when compared with CsA, while retaining equivalent therapeutic efficacy. In the present study, the major metabolic pathways of CsG in the mouse, rat, and dog were investigated using radiolabeled drug substance to determine if interspecies differences in metabolism exist. The results indicated that the major metabolic pathways in these animal species are similar to those previously reported for CsA, including oxidative modifications at amino acids 1, 4, and 9, and concomitant cyclization of amino acid 1 in two of these metabolites. Moreover, the seven major CsG metabolites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observed in animal excreta and/or blood were identical to those identified in humans. The major circulating metabolite in blood was GM9 (9-hydroxylated CsG) in all species. In addition, numerous unidentified minor metabolites were observed. Renal excretion was a minor elimination pathway, with the majority of drug-related material excreted via the fecal route. In conclusion, CsG was found to proceed through the same metabolic pathways in three animal species and humans, and that species differences in metabolism were primarily because of differences in the relative importance of the pathways observed.
环孢素G（CsG；山德士化合物OG 37 - 325）是一种具有强大免疫抑制活性的环十一肽，目前正处于预防移植实体器官排斥反应的临床试验阶段。尽管在结构上与环孢素A（CsA）相似，但动物实验结果表明，与CsA相比，CsG的肾毒性潜力降低，同时保留了相当的治疗效果。在本研究中，使用放射性标记的药物来研究CsG在小鼠、大鼠和犬体内的主要代谢途径，以确定代谢过程中是否存在种间差异。结果表明，这些动物物种中的主要代谢途径与先前报道的CsA的代谢途径相似，包括第1、4和9位氨基酸的氧化修饰，以及其中两种代谢产物中第1位氨基酸的伴随环化。此外，在动物排泄物和/或血液中观察到的七种主要CsG代谢产物（命名为GM19、GM1c9、GM4N9、GM1、GM9、GM1c和GM4N）与在人类中鉴定出的代谢产物相同。所有物种血液中的主要循环代谢产物都是GM9（9 - 羟基化CsG）。此外，还观察到许多未鉴定的次要代谢产物。肾脏排泄是一条次要的消除途径，大多数与药物相关的物质通过粪便途径排泄。总之，发现CsG在三种动物物种和人类中通过相同的代谢途径进行代谢，并且代谢的种间差异主要是由于所观察到的途径相对重要性的差异。
